Natural resistance in vivo is studied by injecting unimmunized mice with tumor cells prelabelled with the thymidine analogue 131 I-iododeoxyuridine. All mice tested were able to recognize and kill leukemia cells which were not identical with self at the major histocompatibility complex (H-2). By monitoring the survival of the prelabelled cells with whole body gamma counting and determining their metastatic distribution, we have found that resistance is manifest as a decrease in survival of the total tumor cell inoculum, and as a failure of the cells to survive in the spleens of mice which are not H-2 identical with the tumor. This resistance is not due to classical immune responses. In some strains of mice resistance is abolished by whole-body irradiation while in others resistance is left intact. Resistance by irradiated mice of the C57BL family depends on H-2D (Hh-1) nonidentity between the host and the graft. The more extensively studied phenomena of haemopoietic graft rejection by irradiated mice and in vitro natural killer activity may be subsets of a more general para-immune resistance system. We propose to extend our studies on natural resistance through genetic analysis of the recognition process, including the nature of the target "antigen", and through determination of the genetic and physiological bases which determine the radio-susceptibility of the rejection process. The mechanisms involved in natural resistance will also be studied. Natural resistance is the earliest manifestation of alloreactivity and its relationship to the subsequent development of the immune response will be determined. A major portion of this project is aimed at determining whether natural resistance is a manifestation of a primitive paraimmune surveillance system against aberrant haemopoietic cells. This will involve studies on resistance to H-2 identical Friend and Abelson leukemia virus induced tumors. In addition to its possible significance in resistance against neoplasia, the study of natural resistance could provide valuable information pertinent to the evolution of adaptive immunity, the control of haemopoiesis and cell interactions, and the physiological functions of the major histocompatibility complex.